Abstract: This project builds upon 15 years of the CHARGE Study, which identified numerous environmental chemicals, nutritional factors, and maternal health conditions that are associated with altered risk for autism spectrum disorder (ASD). This work provided clues about potential pathogenic mechanisms and also produced the first evidence of gene-by-environment (GxE) interaction. In this renewal, CHARGE study will continue to enroll in order to achieve a solid sample size for statistically powerful analyses of both chemical mixtures and GxE interactions. Risk factors of concern are preeclampsia, air pollution, and pesticides, each having replicated evidence of association with ASD. This application departs from the focus on single exposures in isolate, and instead emphasizes multifactorial causation: the focus is on mixtures and interactions. In aim 1, state-of-the-art methods will be applied to understand the impact of exposure mixtures on risk for ASD and if feasible, to identify which component(s) of the mixture most contributes to the overall effects. Aims 2 and 3 address interactions between genes and non-genetic factors (GxE). Aim 2 is to identify common gene variants carried by the mother, which, in combination with early life environmental or medical factors, amplify the risk for ASD, more so than when either factor is assessed separately. The Precision Medicine Array from the Affymetrix platform will be used to generate over 800,000 SNPs that draw heavily from metabolic, pharmacologic, and immune-related regions of the genome. This project then pre-selects subsets of genes biologically relevant to the activity or mechanism of toxicity of each exposure, using annotated gene ontology databases. The resulting GxE analyses are expected to identify common variants that act synergistically with environmental insults, which may have been unremarkable in gene-only studies, or gene studies that emphasized rare variants. Aim 3 examines GxE interactions as in Aim 2, for the child's gene variants. To our knowledge, this will be the first study to evaluate GxE interaction utilizing omics-scale genetics data in a sufficiently powered analysis for detecting interactions. The proposed work moves autism etiologic research into a new direction that bridges separate silos of genetic and environmental research, creating a dynamic interdisciplinary and integrative science. Given shared biologic pathways between some genes and certain environmental exposures, the proposed project has potential to advance etiologic research towards targeted interventions that could reduce risk for ASD or ASD-associated disabilities and improve lives of affected individuals and their families. Additional significance may derive from identification of common variants that have hitherto eluded the traditional genetics enterprise. The long-term impacts may therefore be the emergence of a shift in etiologic research that unifies fragmented disciplinary approaches; major advancement in understanding common variants; and the possibility for public health precision interventions that expand notions of genetic susceptibility to encompass the biochemical milieu of the intrauterine and broader postnatal environment.